1. Field of Invention
The present invention relates to certain aryl(alkyl and alkylene)-N-[(phenoxy and phenylthio)alkyl]pyrrolidines, piperidines, tetrahydropyridines and homopiperidines useful in novel methods of treating cardiovascular dysfunctions, countering effects of histamine in allergies, countering gastric secretion excesses, and inhibiting Type I allergic responses (Gell and Coombs Classification of Immune Responses) in a living mammal body.
2. Information Disclosure Statement
U.S. Pat. No. 3,956,296 and a divisional patent thereof, U.S. Pat. No. 4,032,642 disclose certain compounds among which some would fall within a generic structure as follows: ##STR2## wherein Ar is 4-fluorophenyl or phenyl; R is cyclohexyl; 3-trifluoromethylphenyl, 4-fluorophenyl or phenyl; and A is hydrogen or hydroxy. Certain compounds of the present invention have been found to be metabolites of this group of compounds as explained hereinbelow.
U.S. Pat. No. 3,922,276 discloses compounds among which some would fall within a generic structure as follows: ##STR3## wherein Ar is 4-fluorophenyl or phenyl; and R is cyclohexyl, 4-fluorophenyl, 3-trifluoromethylphenyl, or phenyl. Certain of the compounds of the present invention have been found to be metabolites of this group of compounds as explained hereinbelow.
A copending U.S. patent application Ser. No. 819,701 filed on 1-17-86 by J. R. Shanklin, Jr., et al., and South African Patent No. 86/4522 issued on 2/25/87 disclose compounds among which some would fall within the formula: ##STR4## wherein Ar, R, A, d, n, p, m, B, z, and X are approximately as defined hereinbelow under Formula I, and wherein Y is never as defined hereinbelow under Formula I. It should be understood that the compounds useful in the present invention always have a terminal phenyl group substituted by a Y radical which is distinct from compounds disclosed in prior art. Certain of the compounds of the present invention have been found to be metabolites of certain compounds disclosed in the Shanklin application.
U.S. Pat. No. 4,810,713, issued on 3/7/89 by J. M. Yanni, et al., and South African Patent No. 86/4458 issued on 2/25/87, disclose certain compounds among which some would fall within the generic structure which follows: ##STR5## wherein Ar, R, n, p, m, W and X are approximately as defined hereinbelow under Formula I; A is hydroxy or hydrogen; and Y is never as defined hereinbelow under Formula I. It should be understood that these compounds are a special subclass of the compounds disclosed in the earlier cited U.S. patent application Ser. No. 819,701 of Shanklin, et al.
U.S. Pat. No. 3,806,526 discloses 1-aroylalkyl-4-diphenylmethylpiperidines having antihistaminic, antiallergenic and bronchodilator activity. In contrast, the compounds useful in the present invention have an aryloxyalkyl radical on piperidine and pyrrolidine nitrogen rather than an aroylalkyl radical.
U.S. Pat. No. 4,163,790 discloses compounds which fall within a generic structure as follows: ##STR6## wherein Ar and R are phenyl and p-fluorophenyl and Z is hydrogen, acetyl, p-fluorobenzoylpropyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, phenylcarbamoyl, or N-(.omega.-morpholinoethyl)carbamoyl; A is hydrogen, hydroxy or forms a double bond as indicated by the dotted line. The compounds were active in increasing coronary blood flow; however, the compounds while substituted in the 4-piperidine position and also disclosed in the other above-mentioned patents, differ substantially in structure from the compounds of the present invention in the substitution in the 1-position of the piperidine radical and are not within the scope of generic formulas hereof of compounds for novel treatment methods.
1-Benzyl-(.alpha.,.alpha.-diphenyl)-4-methylenepiperidines of the formula ##STR7## are disclosed in Ger. Offen. 2,800,919 as having anti-convulsant and vasodilating properties. Similar 1-benzyl-(.alpha.,.alpha.-diphenyl)-4-methylenepiperidines of the formula ##STR8## are disclosed in U.S. Pat. No. 4,035,372 as having vasodilating properties.
Piperidines of the general formula ##STR9## where X is H, OH, or forms a double bond to the piperidine ring are disclosed in U.S. Pat. No. 3,965,257 as having antihistamine activity.
4-(Diphenylmethylene)-1-benzylpiperidines of the general formula ##STR10## having hemodynamic, antiarrhythmic and antihistaminic activities are disclosed in U.S. Pat. No. 3,759,928.
U.S. Pat. No. 3,984,557 discloses compounds which fall within a generic structure as follows: ##STR11## wherein R represents loweralkyl, lowercycloalkyl or phenyl-loweralkyl and Y is carbamoyl, cyano or hydrogen, the compounds having utility as antiarrhythmic agents. In the compounds of the present invention, the radical on the 1-position of the cycloalkylamino moiety has an aryloxy, arylamino or an aryl group other than phenyl on the alkyl chain.